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Enhancing the Furosemide Permeability by Papain Minitablets Through a Triple Co-culture In Vitro Intestinal Cell Model

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Abstract

The administration of medicines by the oral route is the most used approach for being very convenient. Although it is the most popular, this route also has absorption, and consequently, bioavailability limitations. In this sense, several pharmacotechnical strategies have been used to improve drug absorption, one of which is the use of permeation promoters. Papain is a very versatile plant enzyme that can be used as a permeation promoter of various active compounds. This study aimed to evaluate the safety of papain and the formulation of native papain minitablets to promote in vitro permeation of furosemide through an innovative biomimetic triple co-culture model of Caco-2, HT29-MTX, and Raji cells. Regarding permeation, furosemide and metaprolol concentrations are determined with HPLC; those are used to calculate Papp. Monolayer integrity was evaluated using TEER and Lucifer Yellow. In the presence of papain, TEER decreased two-fold and the Papp of furosemide increased six-fold. The results suggest that native papain minitablets can be used as therapeutic adjuvants to enhance the permeation of drugs significantly improving bioavailability.

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Abbreviations

ANOVA:

Analysis of Variance

ATCC:

American Type Culture Collection

BAPA:

Nα-benzoyl-DL-arginine 4-nitroanilide hydrochloride

BSA:

Bovine serum albumin

DAPI:

4′,6-diamidine-2′-phenylindole dihydrochloride

DMEM:

Dulbecco’s modified Eagle’s medium

EC:

Enzyme classification

ECACC:

European Collection of Cell Cultures

FBS:

Fetal bovine serum

FURO:

Furosemide

GIT:

Gastrointestinal tract

HBSS:

Hank’s balanced salt solution

Hepes:

4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid

LY:

Lucifer yellow

METO:

Metoprolol

MTT:

(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)

P app :

Permeability coefficient

P-gp:

P-glycoprotein

PPN:

Papain

RPMI:

Roswell Park Memorial Institute

SEM:

Scanning electron microscope

TEER:

Transepithelial electrical resistance

TX-100:

Triton™ X-100

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Acknowledgments

The authors would like to thank Gabriela Nemesio Fazolin from the Center of Chemistry and Environment at the Energy and Nuclear Research Institute for support, Sheila Schuindt do Carmo and Waldir Caldeira from the Center of Images Acquisition and Microscopy at the Institute of Biosciences of University of São Paulo for the acquisition of fluorescence confocal microscopy images. and Rose Eli Grassi Rici from the Advanced Center for Diagnostic Imaging at the School of Veterinary Medicine and Animal Science of University of São Paulo for the acquisition of SEM images.

Funding

This work was supported by São Paulo Research Foundation (FAPESP) (FAPESP grant #2010/10935-9, #2015/19213-0, #2015/19212-3, and #2016/22916-5).

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Authors and Affiliations

  1. Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo (UNIFESP) Campus Diadema, Rua São Nicolau, 210, Centro, Diadema, Sao Paulo, SP09913-030, Brazil

    Fúlvio G. Corazza, Julia V. Ernesto, Felipe A. N. Nambu, Leandro A. Calixto, Vânia R. Leite-Silva, Newton Andréo-Filho & Patricia S. Lopes

  2. Instituto de Pesquisas Energéticas e Nucleares (IPEN-CNEN/SP), Avenida Prof. Lineu Prestes, 2242, Cidade Universitária, Sao Paulo, SP 05508-000, Brazil

    Gustavo H. C. Varca & Daniel P. Vieira

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  1. Fúlvio G. Corazza
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  2. Julia V. Ernesto
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  3. Felipe A. N. Nambu
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Contributions

Resources, formal analysis, investigation, and writing-original draft: F.C., J.E., G.V., and D.V.; investigation: F.N. and L.C.; writing–reviewing and funding acquisition: D.V. and V.L.S.; supervision, resources, funding acquisition, and writing–reviewing: D.V, N.A.F, and P.L.

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Correspondence to Daniel P. Vieira.

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Highlights

Triple co-culture cells mimic intestinal epithelium properties with mucus production.

Papain minitablets increase furosemide permeation by six-fold.

Papain promotes safe and effective oral permeation.

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Corazza, F.G., Ernesto, J.V., Nambu, F.A.N. et al. Enhancing the Furosemide Permeability by Papain Minitablets Through a Triple Co-culture In Vitro Intestinal Cell Model. AAPS PharmSciTech 21, 255 (2020). https://doi.org/10.1208/s12249-020-01796-9

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